Brief Articles
Allogeneic Hematopoietic Stem Cell Transplantation Following
the Use of Hypomethylating Agents among Patients with
Relapsed or Refractory AML: Findings from an International
Retrospective Study
Maximilian Stahl
1, Michelle DeVeaux
2, Pau Montesinos
3,4, Raphaël Itzykson
5,
Ellen K. Ritchie
6, Mikkael A. Sekeres
7, Navneet Majhail
7, John Barnard
7, Nikolai A. Podoltsev
1,
Andrew M. Brunner
8, Rami S. Komrokji
9, Vijaya R. Bhatt
10, Aref Al-Kali
11, Thomas Cluzeau
12,13,
Valeria Santini
14, Gail J. Roboz
6, Pierre Fenaux
5, Mark Litzow
11, Amir T. Fathi
8,
Sarah Perreault
15, Tae Kon Kim
1, Thomas Prebet
1, Norbert Vey
16, Vivek Verma
10,
Guido Kobbe
17, Juan Bergua
18, Josefina Serrano
19, Steven D. Gore
1, Amer M. Zeidan
1,*
1Department of Internal Medicine, Section of Hematology, Yale University School of Medicine, New Haven, Connecticut2Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut
3Department of Medicine, Hospital Universitario y Politécnico de La Fe, University of Valencia, Valencia, Spain 4CIBERONC, Instituto Carlos III, Madrid, Spain
5Saint-Louis Hospital, University Paris 7, Paris, France
6Division of Hematology and Oncology, Weill Cornell Medicine and The New York Presbyterian Hospital 7Leukemia Program, Cleveland Clinic, Cleveland, Ohio
8Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 9Department of Malignant Hematology, Moffitt Cancer Center and Research Institute, Tampa, Florida 10Division of Hematology/Oncology, University of Nebraska Medical Center, Omaha, Nebraska 11Division of Hematology, Mayo Clinic, Rochester, Minnesota
12Côte d’Azur University, Nice Sophia Antipolis University, CHU of Nice, Nice, France 13INSERM U1065, Mediterranean Center of Molecular Medicine, Nice, France 14Division of Hematology, University of Florence, Florence, Italy
15Department of Pharmacy, Yale New Haven Hospital, New Haven, Connecticut 16Department of Hematology, Institut Paoli Calmettes, Marseille, France
17Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany 18Division of Hematology/Oncology, Hospital San Pedro Alcántara, Cáceres, Spain
19Division of Hematology/Oncology, University Hospital Reina Sofía, Cordoba, Spain
Article history: Received 23 January 2018 Accepted 27 March 2018 Key Words: Survival Hypomethylating agents Transplant AML A B S T R A C T
Patients with primary refractory or relapsed acute myeloid leukemia (RR-AML) have very poor prognosis. Due to limited treatment options, some patients are treated with hypomethylating agents (HMAs) due to their tolerability. Little is known about the role of allogeneic hematopoietic stem cell transplantation (HSCT) fol-lowing HMA therapy in this setting. We retrospectively analyzed an international cohort of 655 RR-AML patients who received HMA therapy to study patterns and outcomes with HSCT. Only 37 patients (5.6%) patients un-derwent HSCT after HMA therapy. The conditioning regimen was myeloablative in 57% and nonmyeloablative in 43%. Patients received matched unrelated donor, matched sibling, haploidentical and mismatched unre-lated HSCT in 56%, 24%, 16% and 4% of cases, respectively. Acute GvHD and chronic GvHD were observed in 40% and 17% of patients. While the median OS for the entire cohort of patients was 15.3 months (95% CI 9.5
Financial disclosure: See Acknowledgments on page 1757.
Note: The results of this research were presented at American Society of Hematology, Atlanta, GA, December 2017.
* Correspondence and reprint requests: Amer M. Zeidan, MBB, MHS, Section of Hematology, Department of Internal Medicine, Yale School of Medicine, 333 Cedar St, New Haven, CT 06510-3222.
E-mail address:amer.zeidan@yale.edu(A.M. Zeidan). https://doi.org/10.1016/j.bbmt.2018.03.025
1083-8791/© 2018 American Society for Blood and Marrow Transplantation.
Biology of Blood and
Marrow Transplantation
– 21.7 months), OS reached 29.7 months (95% CI 7.01 – not-reached) for patients who achieved a complete remission (CR) to HMA and no intervening therapies between HMA therapy and HSCT. Our study suggests that HMA therapy can effectively bridge some patients with RR-AML to HSCT.
© 2018 American Society for Blood and Marrow Transplantation.
INTRODUCTION
Patients with primary refractory and relapsed (RR) acute myeloid leukemia (AML), particularly older adults, have dismal outcomes and limited therapeutic options are available[1]. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potentially curative treatment in this setting[2,3]. However, achieving disease control is generally necessary for successful HSCT outcomes. Intensive chemotherapy is the commonly used modality to achieve CR for patients with RR AML; however, complete remission (CR) rates generally do not exceed 20% to 40% and intensive therapy is associated with increased risks of mortality and morbidity as well as pro-longed hospitalization. Given their tolerability, hypomethylating agents (HMAs) have been used in pa-tients with AML, usually in frontline setting, who are unfit for intensive chemotherapy[1]. In a prior multicenter study, we have shown that HMAs result in CR/CR with incomplete count recovery (CRi) in 16% of patients with RR AML while offering the opportunity of outpatient therapy and lower risk of therapy-related complications[4]. Most of the data re-garding transplant outcomes among patients with RR AML comes from trials and analyses of patients who received in-tensive salvage chemotherapy [5]. Several intensive chemotherapy regimens have been studied; however, there is no clear evidence of superiority of any particular regimen [5]. In contrast, little is known about the transplant out-comes for those patients with RR AML who are treated with HMA as salvage therapy before transplantation.
METHODS
Using a large multicenter international database, we analyzed charac-teristics and clinical outcomes of the subgroup of RR AML patients who underwent HSCT after HMA salvage therapy. Data of patients treated with HMAs for RR AML were collected for a period spanning 2006 to 2016, from 7 centers in the United States and 4 centers in Europe. For the subgroup of patients who underwent HSCT after HMA therapy, we assessed type of graft and conditioning regimen, lines of therapy post-HMA and before HSCT, a well as any post-HSCT therapies. Furthermore, we analyzed the rate and se-verity of acute and chronic graft-versus-host disease (GVHD) as well as 30-day and long-term mortality post-transplantation and their respective predictors. Kaplan-Meier methods were used to estimate overall survival (OS) from the start of HMA therapy to death or end of follow-up.
RESULTS
Of 655 patients in the database, 16% achieved a CR/CRi with HMA therapy, and only 37 patients (5.6% of the entire cohort) underwent HSCT at one point after receiving HMA salvage therapy (Table 1). Of these patients, 16 (43.2%) had relapsed and 21 (56.8%) had primary refractory AML. At the time of HMA therapy, only 1 patient had favorable risk karyo-type, whereas 69% and 23% had intermediate-risk and poor-risk karyotypes, respectively. Azacitidine and decitabine were used in 34% and 66% of patients, respectively. Patients had received a median of 1 line of therapy (range, 1 to 7) before HMA therapy. Of all patients who underwent HSCT, 23 (62%) had achieved a response (CR, CRi, or hematologic improve-ment [HI]) to HMA therapy whereas the other 14 (38%) did not. Twenty-four (65%) patients went directly to HSCT after completing HMA therapy while 13 (35%) patients received additional therapy between HMA therapy and HSCT (Table 2).
Of patients receiving no additional therapies between HMA and HSCT, a total of 16 patients had responded to HMA therapy (CR= 7, CRi = 8, HI = 1). Of patients who received some type of post-HMA therapy before HSCT, 7 patients had achieved a prior response to HMA (CR= 4, CRi = 2, HI = 1).
The median duration between last day of HMA therapy and HSCT was 50 days (range, 6 to 210 days). Approximate-ly 57% of patients received myeloablative conditioning therapy while the other 43% received nonmyeloablative condition-ing regimens. Most patients received a matched unrelated donor transplant (56%) or a matched sibling transplant (24%), whereas 16% and 4% of patients received a haploidentical or a mismatched unrelated HSCT, respectively (Table 2).
Acute GVHD was observed in 40% of patients, with 75% developing grade of 1 or 2 GVHD and 25% developing grade 3 or 4 GVHD. Acute GVHD affected skin (30%), mouth (10%), gastrointestinal tract (45%), and liver (15%). Furthermore, 17% of patients developed chronic GVHD, which was limited in Table 1
Patient Characteristics of the 37 Transplanted Patients Patient characteristics
Male/female sex 17/20 (46/54)
Age, yr 56 (22–71)
Disease status
Relapsed 16 (43.2)
Primary treatment refractory 21 (56.8)
Karyotype risk Favorable 1 (8) Intermediate 9 (69) Poor 3 (23) Azacitidine/decitabine 11/21 (34/66) Response to HMA 23 (62) CR 11 (30) CRi 10 (27) HI 2 (5) No response to HMA 14 (38)
Therapy between stop of HMA therapy and HSCT
Yes/no 13/24 (35/65)
Type of therapy administered (18 therapies prescribed to 13 patients): CPX 5 (27.8) Cytarabine 5 (27.8) Clofarabine 3 (16.8) CLAG 2 (11.1) MEC 1 (5.6) FLAG Ida 1 (7.7) Cytoxan/etoposide 1 (5.6) Therapy after HSCT Yes/no 7/30 (19/81)
Type of therapy administered (13 therapies prescribed to 7 patients): Azacitidine, decitabine 6 (46.2) Cytarabine 2 (15.4) Hydroxyurea 2 (15.4) SGI-110 1 (7.7) ASP-2215 1 (7.7) Sorafenib 1 (7.7)
Data are presented as n/n (%), mean (range), or n (%).
CPX-351 indicates liposomal formulation containing a fixed combination of cytarabine and daunorubicin in a 5:1 molar ratio; CLAG, cladribine, cytarabine, and filgrastim; MEC: mitoxantrone, etoposide and cytarabine; FLAG, fludarabine, cytarabine, granulocyte colony-stimulating factor; SGI-110, guadecitabine; ASP-2215, gilteritinib.
75% and extensive in 25% of patients (Table 2). Chronic GVHD most commonly affected skin (40%), but also affected eyes and mouth (20%), gastrointestinal tract (20%), and liver (20%). After HSCT, 7 (19%) patients received further lines of therapy, with epigenetic therapy (HMA or histone deacetylase inhibitor therapy) (58%) being most commonly used whereas chemo-therapy was rarely used (8%).
The median OS for the entire cohort of 37 patients who underwent HSCT after HMA therapy was 15.3 months (95% confidence interval [CI], 9.5 to 21.7 months) from the start of HMA therapy. This was statistically significantly longer than the median OS for all other 618 patients, who did not receive a HSCT after HMA therapy (OS, 6.4 months; 95% CI, 5.7 to 6.9 months; P< .0001). The median OS was 14.6 months (95% CI, 9.5 months to not reached) for patients with no therapies ad-ministered between HMA and HSCT and 15.3 months (95% CI, 9.4 months to not reached) for patients with at least 1 therapy in between HMA and HSCT, respectively (P= .3) (Figure 1A).
For patients, who underwent subsequent HSCT without intervening therapies between HMA and HSCT, median OS was 16.8 months (95% CI, 9.5 months to not reached) for the 16 patients who achieved a response to HMA therapy (CR/ CRi/HI), whereas it was 14.5 months (95% CI, 6.7 months to not reached; P= .4) for the 8 patients with either stable disease or progressive disease (Figure 1B).
For patients without intervening therapies between HMA and HSCT, median OS was 29.7 months (95% CI, 7 months to not reached) for patients who achieved a CR to HMA and 14.6 months (95% CI, 9.47 months to not reached) for those not achieving CR (P= .6).
DISCUSSION
In summary, in one of the largest reported cohorts of pa-tients with RR AML treated with HMAs, we determined that a minority of patients underwent HSCT after completion of HMA therapy.
While the median OS of the patients who underwent HSCT after HMA therapy was significantly longer compared with patients who did not undergo HSCT, only about 25% of the 24 patients who went to HSCT directly after HMA therapy were long term survivors (reached a plateau on the Kaplan-Meier survival curve), which translates into just 6 patients of the original 655-person cohort (<1%). Importantly, the OS for patients who achieved a CR with HMAs and went direct-ly to HSCT was not statisticaldirect-ly significantdirect-ly different from patients who achieved a CR with HMAs but did not undergo HSCT (29.7 months versus 25.3 months; P= .8). Further-more, it did not seem to make a difference whether patients achieved a response to HMA therapy or not and whether pa-tients went directly to HSCT after HMA therapy or had any other therapy after receiving HMA and before HSCT (Figure 1). These findings could argue against a benefit specific to HMA therapy when used as a bridge therapy to HSCT. While patients who achieved a CR with HMAs and thereafter un-derwent HSCT without intervening therapy had a median OS reaching 30 months, this subgroup was too small to make any conclusions whether they had a statistically significantly pro-longed OS compared with patients who did not achieve a CR with HMA therapy.
Our study indicates that while HMAs can allow outpa-tient administration with lower toxicity compared with salvage intensive chemotherapy and can be used as a bridge Table 2
Transplant Characteristics for Patients who underwent HSCT after HMA for RR AML
All Patients (N= 37) Patients with no Subsequent Therapies between HMA and HSCT (n= 24)
Patients with Subsequent Therapies between HMA and HSCT (n= 13)
Type of graft (n= 25)
Matched sibling 6 (24) 4 (25) 2 (22.2)
Matched unrelated donor 14 (56) 9 (56.2) 5 (55.6)
Mismatched unrelated 1 (4) 0 (0) 1 (11.1)
Haplotransplant 4 (16) 3 (18.8) 1 (11.1)
Type of conditioning regimen (n= 14)
Ablative 8 (57.1) 7 (63.6) 1 (33.3) Nonablative 6 (42.9) 4 (36.4) 2 (66.7) Acute GVHD: Presence of acute GVHD (n= 25) 10 (40) 6 (40) 4 (40) Grade of acute GVHD (n= 8) 1 3 (37.5) 2 (50) 1 (25) 2 3 (37.5) 1 (25) 2 (50) 3 1 (12.5) 0 (0) 1 (25) 4 1 (12.5) 1 (25) 0 (0)
Organ affected in acute GVHD (n= 20)
Skin 6 (30) 4 (33.3) 2 (25) Eyes 2 (10) 2 (16.7) 0 (0) Gut 9 (45) 5 (41.7) 4 (50) Liver 3 (15) 1 (8.3) 2 (25) Chronic GVHD Presence of chronic GVHD (n= 24) 4 (16.7) 3 (21.4) 1 (10) Severity of chronic GVHD (n= 4) Limited 3 (75) 3 (100) 0 (0) Extensive 1 (25) 0 (0) 1 (100)
Organ affected in chronic GVHD (n= 5)
Skin 2 (40) 2 (66.7) 0 (0)
Mouth 1 (20) 1 (33.3) 0 (0)
Gut 1 (20) 0 (0) 1 (50)
Liver 1 (20) 0 (0) 1 (50)
to HSCT, only a minority of patients with RR AML were able to undergo transplantation and the long survival rate was quite limited. As most patients do very poorly regardless of HMA response and regardless of receiving HSCT, improved treat-ments are urgently needed for patients with RR AML. Combining HMAs with investigational therapies could lead to better outcomes in this difficult to treat patient population. ACKNOWLEDGMENTS
The authors acknowledge the Frederick A. DeLuca Foun-dation for financial support.
Financial disclosure: The authors have nothing to disclose. Conflict of interest statement:
P.M.
Celgene Corporation, Honoraria and Research Funding R.I.
Janssen, Research Funding Novartis, Research Funding E.K.R.
Novartis, Consultancy, Other: Research Funding to my in-stitution, and Travel and Speakers Bureau
Incyte, Consultancy or Advisory role and Speakers Bureau Celgene, Consultancy or Advisory role, Travel and Speak-ers Bureau
Novartis, Consultancy or Advisory role, Travel and Speak-ers Bureau
ARIAD, Speakers Bureau
Pfizer, Consultancy or Advisory role and Research Funding to my institution
Astellas Pharma, Research Funding to my institution
Bristol-Myers Squibb, Research Funding to my institution NS Pharma, Research Funding to my institution
M.A.S.
Celgene, Membership on an entity’s Board of Directors or Advisory Committees
Millenium-Takeda, Membership on an entity’s Board of Di-rectors or Advisory Committees
Opsona, Membership on an entity’s Board of Directors or Advisory Committees
N.A.P.
CTI BioPharma/Baxalta, Consultancy Alexion, Consultancy
Ariad, Consultancy Incyte, Consultancy
Boehringer Ingelheim, Astellas Pharma, Daiichi Sankyo, Sunesis Pharmaceuticals, Celator, Pfizer, Astex Pharmaceu-ticals, All: Research Funding to my institution
A.M.B.
Celgene, Research Funding to my institution Takeda, Research Funding to my institution R.S.K.
Celgene, Honoraria, Consultancy and Travels
Novartis, Honoraria, Consultancy, Speakers Bureau and Travels
Alexion Pharmaceuticals, Speakers Bureau and Travels Abbvie, Stock or Other Ownership
Incyte, Research Funding to my institution and Travels Celgene, GlaxoSmithKline, Eleos, Boehringer Ingelheim, All: Research Funding to my institution
A
B
14.6 months
95% CI: 9.5 months – not-reached
15.3 months 95% CI: 9.4 months– not-reached
log-rank p-value = 0.3
16.8 months 95% CI: 9.5 months – not-reached
14.5 months 95% CI: 6.7 months –not reached
log-rank p-value = 0.4
Figure 1. Probability of overall survival from start of HMA therapy. A: For patients who directly went to HSCT vs. patients, who received at least one more line of therapy between HMA and HSCT. B: For patients, who directly went to HSCT stratified by having a response (CR,CRi,HI) vs. no response (SD, PD) to HMA therapy.
A.A.-K.
Novartis, Onconova Therapeutics, Celgene, Bristol-Myers Squibb, Astex Pharmaceuticals, Ambit BioSciences, All: Re-search Funding to my institution
V.S.
Celgene, Honoraria and Research Funding Janssen, Consultancy and Honoraria Novartis, Honoraria
Abbvie, Consultancy and Membership on an entity’s Board of Directors or Advisory Committees
Amgen, Membership on an entity’s Board of Directors or Advisory Committees
Otsuka, Consultancy A.T.F.
Seattle Genetics, Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees and Re-search Funding
Juno, Membership on an entity’s Board of Directors or Ad-visory Committees
Takeda, Research Funding
Celgene, Consultancy, Honoraria, Membership on an en-tity’s Board of Directors or Advisory Committees and Research Funding
Agios, Consultancy, Honoraria and Membership on an en-tity’s Board of Directors or Advisory Committees
Medimmune, Consultancy and Membership on an enti-ty’s Board of Directors or Advisory Committees
Amgen, Consultancy and Membership on an entity’s Board of Directors or Advisory Committees
Pfizer, Honoraria G.J.R.
All consultancy: AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuti-cals, Janssen PharmaceutiPharmaceuti-cals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace, Boehringer Ingelheim, GlaxoSmithKline, Shire, Astex Pharmaceuticals, Cellectis, Sunesis Pharmaceuticals
All Research Funding to my institution: Abbvie, Agios, Astex Pharmaceuticals, Celgene, CTI, Karyopharm Therapeutics, MedImmune, MEI Pharma, Moffitt, Novartis, Onconova Ther-apeutics, Pfizer, Sunesis Pharmaceuticals, Tensha TherTher-apeutics, Cellectis
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Cellectis, Research Funding P.F.
Amgen, Honoraria and Research Funding Astex, Honoraria and Research Funding Celgene, Honoraria and Research Funding Janssen, Honoraria and Research Funding M.L.
Amgen, Research Funding, Honoraria, Consultancy and Travels
Novartis Pharmaceuticals, Research Funding Astellas Pharma, Research Funding
Actinium Pharmaceuticals, Research Funding N.V.
Amgen, Honoraria and Consultancy Celgene, Honoraria and Consultancy Novartis, Honoraria and Consultancy Roche, Honoraria and Consultancy Servier, Honoraria and Consultancy A.M.Z.
All Research Funding to my institution: Celgene, Pfizer, Incyte, ADC Therapeutics, Medimmune, Takeda, Abbvie, and Boehringer Ingelheim.
All Consultancy and Honoraria: AbbVie, Ostuka, Pfizer, Gilead, Celgene, Ariad, Incyte, Agios, Novartis, Takeda, Daiichi Sankyo, and Boehringer Ingelheim.
Speaking/Honoraria: Takeda, Speakers Bureau No other potential conflicts are reported.
SUPPLEMENTARY DATA
Supplementary data related to this article can be found online atdoi:10.1016/j.bbmt.2018.03.025.
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